Material for buffered resorbable internal fixation devices and method for making same

Abstract

A bioerodible implantable material, comprising a bioerodible polymer that produces acidic products upon hydrolytic degradation, and a buffering compound that buffers the acidic products and maintains the local pH within a desired range. The buffer compound acts to reduce the inflammatory foreign body response generated by the acidic products and reduces the sterile abscess condition that occurs at the site of the bioerodible implant materials of the prior art. Materials made according to the invention may be used for internal fixation devices (IFDs) for bone repair.

Claims

1. A bioerodible implantable material, comprising:

a bioerodible polymer, said bioerodible polymer producing acidic products upon hydrolytic degradation; and

a buffer in sufficiently high concentration so as to buffer said acidic products within a pH range within which physiological irritation, inflammation, and swelling (sterile abscess formation) caused by said unbuffered acidic products in vivo is prevented or ameliorated.

2. The bioerodible implantable material of claim 1, wherein said bioerodible polymer is selected from the group consisting of polydioxanone, poly(.epsilon.-caprolactone), polyanhydride, poly(ortho ester), copoly(ether-ester), polyamide, polylactone, poly(propylene fumarate), and combinations thereof.

3. The bioerodible implantable material of claim 1, wherein said bioerodible polymer comprises poly(lactide-co-glycolide) with a lactide to glycolide ratio in the range of 0:100% to 100:0% inclusive.

4. The bioerodible implantable material of claim 1, wherein said buffer is the salt of an inorganic acid.

5. The bioerodible implantable material of claim 1, wherein said buffer is the salt of an organic acid.

6. The bioerodible implantable material of claim 1, wherein said buffer is a polymer comprising at least one basic group.

7. The bioerodible implantable material of claim 6, wherein said polymer comprising at least one basic group is selected from the group consisting of hydrolyzable polyamines, hydrolyzable polyesters, vinyl polymers, and copolymers of acrylic acid.

8. The bioerodible implantable material of claim 6, wherein said at least one basic group is covalently bonded within said polymer.

9. The bioerodible implantable material of claim 1, wherein said buffer is a compound which, on exposure to water, hydrolyzes to form a base.

10. The bioerodible implantable material of claim 9, wherein the quantity of said base generated upon hydrolysis is equivalent to the quantity of said acidic products formed by said bioerodible polymer hydrolysis.

11. The bioerodible implantable material of claim 1, wherein said buffer is selected from the group consisting of carbonates, phosphates, acetates, succinates, and citrates.

12. The bioerodible, implantable material of claim 1, wherein said buffer is a calcium salt.

13. The bioerodible, implantable material of claim 1, wherein said buffer is calcium carbonate.

14. The bioerodible implantable material of claim 1, wherein the parent acid of said buffer has an acid dissociation constant that is smaller than the acid dissociation constant of said acidic products.

15. The bioerodible implantable material of claim 1, wherein said buffer has a hydrolysis constant that is greater than the hydrolysis constant of said acidic products.

16. The bioerodible implantable material of claim 1, wherein said pH range is 6.8-7.4.

17. A method of making a buffered bioerodible, implantable material, comprising the steps of:

dissolving a bioerodible polymer in a solvent, said bioerodible polymer producing acidic products upon hydrolytic degradation;

mixing a buffer with said dissolved bioerodible polymer, said buffer present in sufficently high concentration so as to buffer said acidic products within a pH range within which physiological irritation, inflammation, and swelling (sterile abscess formation) caused by said unbuffered acidic products in vivo is prevented or ameliorated;

casting said mixture; and

evaporating said solvent of said mixture to produce a buffered bioerodible implantable material.

18. The method of claim 17, wherein said bioerodible polymer is selected from the group consisting of polydioxanone, poly(.epsilon.-caprolactone), polyanhydride, poly(ortho ester), copoly(ether-ester), polyamide, polylactone, poly(propylene fumarate), and combinations thereof.

19. The method of claim 17, wherein said bioerodible polymer comprises poly(lactide-co-glycolide) with a lactide to glycolide ratio in the range of 0:100% to 100:0% inclusive.

20. The method of claim 17, wherein said buffer is the salt of an inorganic acid.

21. The method of claim 17, wherein said buffer is the salt of an organic acid.

22. The method of claim 17, wherein said buffer is a polymer comprising at least one basic group.

23. The method of claim 17, wherein said buffer is a compound which, on exposure to water, hydrolyzes to form a base.

24. The method of claim 17, further comprising the step of milling said buffer in said polymer solution.

25. The method of claim 17, further comprising the step of processing said buffered bioerodible implantable material into a desired form.

26. The method of claim 17, further comprising the step of coating said buffer with a polymeric material that degrades at a slower rate than PLGA.

27. The method of claim 17, further comprising the steps of:

providing a first solution comprising a soluble calcium salt;

providing a second solution comprising a soluble ionic carbonate;

mixing said first solution and said second solution to form a calcium carbonate precipitate; and

collecting said calcium carbonate precipitate for use as said buffer.

28. The method of claim 27, wherein said calcium carbonate precipitate comprises calcite and aragonite.

29. The method of claim 17, further comprising the steps of:

providing a salt comprising a metal ion and a carboxylate ion; and

combusting said salt to form said buffer.

30. The method of claim 29, wherein said combusting step takes place at temperatures between 450.degree. and 1000.degree. C., inclusive.

31. A method for making a buffered bioerodible implantable PLGA material, comprising the steps of:

providing bioerodible polymer particles having a specific size, said bioerodible polymer producing acidic products upon hydrolytic degradation;

providing buffer particles having a specific size, said buffer particles comprising a buffer present in sufficently high concentration so as to buffer said acidic products within a pH range within which physiological irritation, inflammation, and swelling (sterile abscess formation) caused by said unbuffered acidic products in vivo is prevented or ameliorated; and

mixing said bioerodible polymer particles and said buffer particles in a predetermined proportion.

32. The method of claim 31, wherein said bioerodible polymer particles comprise poly(lactide-co-glycolide) with a lactide to glycolide ratio in the range of 0:100% to 100:0% inclusive.

33. The method of claim 31, wherein said buffer is the salt of an inorganic acid.

34. The method of claim 31, wherein said buffer is the salt of an organic acid.

35. The method of claim 31, wherein said buffer is a polymer comprising at least one basic group.

36. The method of claim 31, wherein said buffer is a compound which, on exposure to water, hydrolyzes to form a base.

37. The method of claim 31, further comprising the step of processing said buffered bioerodible implantable material into a desired form.

38. The method of claim 31, further comprising the step of coating said buffer particles with a polymeric material that degrades at a slower rate than PLGA.

39. The method of claim 31, further comprising the steps of:

providing a first solution comprising a soluble calcium salt;

providing a second solution comprising a soluble ionic carbonate;

mixing said first solution and said second solution to form a calcium carbonate precipitate; and

collecting said calcium carbonate precipitate for use as said buffer particles.

40. The method of claim 39, wherein said calcium carbonate precipitate comprises calcite and aragonite.

41. The method of claim 31, further comprising the steps of:

providing a salt comprising a metal ion and a carboxylate ion; and

combusting said salt to form said buffer.

42. The method of claim 41, wherein said combusting step takes place at temperatures between 450.degree. and 1000.degree. C., inclusive.

43. A method for making a buffered bioerodible implantable material, comprising the steps of:

providing an open celled bioerodible foam polymer of controlled density, said bioerodible foam polymer producing acidic products upon hydrolytic degradation;

providing a buffer dissolved in a solvent, said foam polymer not soluble in said solvent, present in sufficiently high concentration so as to buffer said acidic products within a pH range within which physiological irritation, inflammation, and swelling (sterile abscess formation) caused by said unbuffered acidic products in vivo is prevented or ameliorated;

loading said buffer compound dissolved in said solvent into said PLGA foam polymer; and

freeze drying said buffer loaded foam polymer to remove said solvent.

44. The method of claim 43, further comprising the step of processing said buffered bioerodible implantable material into a desired form.

45. The method of claim 43, further comprising the step of coating said buffer particles with a polymeric material that degrades at a slower rate than PLGA.

46. The method of claim 43, wherein said bioerodible polymer comprises poly(lactide-co-glycolide) with a lactide to glycolide ratio in the range of 100:0 to 0:100 inclusive.

47. The method of claim 43, wherein said buffer is the salt of an inorganic acid.

48. The method of claim 43, wherein said buffer is the salt of an organic acid.

49. The method of claim 43, wherein said buffer is a polymer comprising at least one basic group.

50. The method of claim 43, wherein said buffer is a compound which, on exposure to water, hydrolyzes to form a base.

51. A method for making a buffered bioerodible implantable material, comprising the steps of:

providing a bioerodible polymer having a first melting temperature, said bioerodible polymer producing acidic products upon hydrolytic degradation;

providing buffer particles comprising buffer material coated with a protective polymer, said protective polymer having a second melting temperature, said second melting temperature greater than said first melting temperature, said buffer particles comprising a buffer present in sufficiently high concentration so as to buffer said acidic products within a pH range within which physiological irritation, inflammation, and swelling (sterile abscess formation) caused by said unbuffered acidic products in vivo is prevented or ameliorated;

heating said bioerodible polymer to a temperature between said first melting temperature and said second melting temperature;

mixing said heated bioerodible polymer and said coated buffer particles; and

cooling said mixture.

52. The method of claim 51, further comprising the step of processing said buffered bioerodible implantable material into a desired form.

53. The method of claim 51, wherein said bioerodible polymer comprises poly(lactide-co-glycolide) with a lactide to glycolide ratio in the range of 100:0 to 0:100 inclusive.

54. The method of claim 51, wherein said buffer is the salt of an inorganic acid.

55. The method of claim 51, wherein said buffer is the salt of an organic acid.

56. The method of claim 51, wherein said buffer is a polymer comprising at least one basic group.

57. The method of claim 51, wherein said buffer is a compound which, on exposure to water, hydrolyzes to form a base.

58. The method of claim 51, further comprising the steps of:

providing a first solution comprising a soluble calcium salt;

providing a second solution comprising a soluble ionic carbonate;

mixing said first solution and said second solution to form a calcium carbonate precipitate; and

collecting said calcium carbonate precipitate for use as said buffer.

59. The method of claim 58, wherein said calcium carbonate precipitate comprises calcite and aragonite.

60. The method of claim 51, further comprising the steps of:

providing a salt comprising a metal ion and a carboxylate ion; and

combusting said salt to form said buffer material.

61. The method of claim 60, wherein said combusting step takes place at temperatures between 450.degree. and 1000.degree. C., inclusive.